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Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

ABSTRACT: Aberrant dopamine D(4) receptor function has been implicated in mental illnesses, including schizophrenia and attention deficit-hyperactivity disorder. Recently we have found that D(4) receptor exerts an activity-dependent bi-directional regulation of AMPA receptor (AMPAR)-mediated synaptic currents in pyramidal neurons of prefrontal cortex (PFC) via the dual control of calcium/calmodulin kinase II (CaMKII) activity. In this study, we examined the signaling mechanisms downstream of CaMKII that govern the complex effects of D(4) on glutamatergic transmission. We found that in PFC neurons at high activity state, D(4) suppresses AMPAR responses by disrupting the kinesin motor-based transport of GluR2 along microtubules, which was accompanied by the D(4) reduction of microtubule stability via a mechanism dependent on CaMKII inhibition. On the other hand, in PFC neurons at the low activity state, D(4) potentiates AMPAR responses by facilitating synaptic targeting of GluR1 through the scaffold protein SAP97 via a mechanism dependent on CaMKII stimulation. Taken together, these results have identified distinct signaling mechanisms underlying the homeostatic regulation of glutamatergic transmission by D(4) receptors, which may be important for cognitive and emotional processes in which dopamine is involved.

SUBMITTER: Yuen EY

PROVIDER: S-EPMC3137069 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Yuen Eunice Y EY Yan Zhen Z

The Journal of biological chemistry 20110527 28

Aberrant dopamine D(4) receptor function has been implicated in mental illnesses, including schizophrenia and attention deficit-hyperactivity disorder. Recently we have found that D(4) receptor exerts an activity-dependent bi-directional regulation of AMPA receptor (AMPAR)-mediated synaptic currents in pyramidal neurons of prefrontal cortex (PFC) via the dual control of calcium/calmodulin kinase II (CaMKII) activity. In this study, we examined the signaling mechanisms downstream of CaMKII that g ...[more]

PMID: 21622557

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Project description:Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid beta (Abeta) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which Abeta oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease.

Dataset Information

Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Publications

Cellular mechanisms for dopamine D4 receptor-induced homeostatic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

Similar Datasets

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